Pain is generally classified into three groups: physiological pain such as that caused when a needle pricks skin; inflammatory pain; and neuropathic pain. The neuropathic pain is due to nerve injury and is an intractable disease accompanied by symptoms of spontaneous pain, hyperalgesia, and allodynia, etc. Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids such as morphine often do not exert their analgesic effect on the neuropathic pain. While little is known about pathogenesis of such neuropathic pain, emerging studies of persistent allodynia caused by nerve injury indicate involvement of spinal glutamate receptors, suggesting that regulation of the signal transduction mediated by receptors would result in inhibition of neuropathic pain.
In a related study, acromelic acids (isomeric acromelic acid A and B which are different in the substitution pattern), isolated from a poisonous mushroom, Clitocybe acromelalga, have been found to induce severe allodynia by intrathecal administration in mice (Non-patent document 1). Acromelic acids are known to induce neuronal excitotoxicity in the central nervous system.

The above-mentioned acromelic acids include a structure like that of glutamic acid, and therefore, are considered to exert their activities through glutamate receptors. However, acromelic acids are also reported to show selectivity to lower spinal cord and specifically destroy spinal interneuron, the first relay point in pain-transmission. These findings are inconsistent with what has been reported for the other glutamate receptor agonists in in vivo behavioral and pathological effects, suggesting the possible existence of novel acromelic acid receptor. Indeed, there are some reports suggesting a novel acromelic acid receptor based on in vivo behavioral and pathological studies of acromelic acids. Nevertheless, the details are still unknown.
Thus, acromelic acids are useful compounds as an important biochemical tool for investigating the pathogenesis of neuropathic pain and elulcidating the function of various neural receptors including glutamate receptors and the like. It is, however, extremely laborious to extract acromelic acids from Clitocybe acromelalga. Moreover, only a trace of acromelic acids can be obtained, far from the amount required for use as an experiment tool (Non-patent documents 2 and 3).
Although there have been some reports of chemical synthesis of acromelic acids, the proline framework of the compounds possessing asymmetric carbons at the 2, 3 and 4-positions makes it difficult to synthesize them in large quantity with complete control of stereochemistry, especially in stereoselective introduction of the carbon substituent at the 4-position of the proline framework.
In order to explore the mechanism of action of neural receptors, the present inventors synthesized the following proline analogue (a) having a similar structure to acromelic acids but with an azide group introduced as a photo-sensitive probe, and examined its physiological activity. As a result, it was found that the compound exhibits the same degree of allodynia-inducing activity as that of acromelic acids (Non-patent document 4).

The present inventors further developed proline analogues that exhibit allodynia-inducing activity and methods for preparing them, and have already filed a patent application thereof (Japanese Application No. 2005-347711). With that invention, a large amount of proline analogues that exhibit allodynia-inducing activity can be readily provided, which may serve in elucidating the molecular mechanism of neuropathic pain and function of neurol receptors including glutamate receptors.
Generally, in order to understand biosignal transduction mechanism, not only agonists that trigger the activation of certain receptors but also antagonists that inhibit the receptor function are a useful tool and thus they needs to be developed. Furthermore, creation of compounds which can inhibit the action of acromelic acids provides not only molecular probes for elucidation of the receptor function involved in neuropathic pain, but also possible therapeutic agents or seeds compounds for neuropathic pain treatment. However, any compounds that exhibit such inhibitory activity have not been discovered. In Patent documents 1 and 2, although the description is found that some proline analogues, which are similar to but distinct from the pyrrolidine analogues of the present invention, can be used as therapeutic agents for treatment of pain disorders, any experimental data demonstrating their pharmacological effects used in the treatment of pain disorders are not provided (Patent documents 1 and 2).    [Non-patent document 1]
British Journal of Pharmacology, 2004, 142, 679-688    [Non-patent document 2]
Tetrahedron Letters 1983, 24, 939-942    [Non-patent document 3]
Journal of the American Chemical Society 1988, 110, 4807-4815    [Non-patent document 4]
Tetrahedron Letters 2004, 45, 3933-3936    [Patent document 1]
WO2004/039367    [Patent document 2]
Japanese Patent Publication No. 2006-516115